Combined Meningococcal Conjugates With Common Carrier Protein

Abstract

Carrier-induced epitopic suppression is of particular concern where multiple conjugates with the same carrier protein are administered simultaneously. To avoid the suppression, the invention minimises the amount of unconjugated carrier protein in a vaccine. The invention provides a composition for immunising a patient against a disease caused by Neisseria meningitidis, wherein (1) the composition comprises conjugates for at least two of the four meningococcal serogroups A, C, W135 and Y, where at least two of the conjugates have a common carrier protein; and (2) the composition includes the common carrier in an unconjugated form at less than 10 μg / ml.

Description

TECHNICAL FIELD[0001]This invention concerns vaccines against Neisseria meningtitidis. In particular, it concerns vaccines based on conjugated capsular saccharides from multiple meningococcal serogroups.BACKGROUND ART[0002]Based on the organism's capsular polysaccharide, twelve serogroups of N. meningitidis have been identified (A, B, C, H, I, K, L, 29E, W135, X, Y and Z). Group A is the pathogen most often implicated in epidemic disease in sub-Saharan Africa. Serogroups B and C are responsible for the vast majority of cases in USA and in most developed countries. Serogroups W135 and Y are responsible for the remaining cases in USA and developed countries.[0003]A bivalent vaccine of capsular polysaccharides from serogroups A+C is available as the product Mencevax AC™, and tetravalent mixtures of the saccharides from serogroups A+C+Y+W135 are available as the products Mencevax ACWY™ and Menomune™ [1-3]. Although effective in adolescents and adults, these vaccines induces a poor immun...

AI Technical Summary

Benefits of technology

[0019]Conjugation is used to enhance the immunogenicity of saccharides, as it converts them from T-independent antigens to T-dependent antigens, thus allowing priming for immunological memory. Conjugation is particularly useful for pediatric vaccines [e.g. ref. 17] and is a well known technique [e.g. reviewed in refs. 18 to 27].

[0025]The saccharides used according to the invention are preferably shorter than the native capsular saccharides seen in bacteria. Thus the saccharides are preferably depolymerised, with depolymerisation occurring after purification but before conjugation. Depolymerisation reduces the chain length of the saccharides. A preferred depolymerisation method involves the use of hydrogen peroxide [7]. Hydrogen peroxide is added to a saccharide (e.g. to give a final H2O2 concentration of 1%), and the mixture is then incubated (e.g. at about 55° C.) until a desired chain length reduction has been achieved. Another depolymerisation method involves acid hydrolysis [8], with preferred depolymerised saccharides in conjugates of the invention having the following range of average degrees of polymerisation: A=10-20; C=12-22; W135=15-25; Y=15-25. Other depolymerisation methods are known to the skilled person. The saccharides used to prepare conjugates for use according to the invention may be obtainable by any of these depolymerisation methods. Depolymerisation can be used in order to provide an optimum chain length for immunogenicity and / or to reduce chain length for physical manageability of the saccharides.

[0047]Other methods for measuring unconjugated carrier protein may involve capillary electrophoresis [74] (e.g. in free solution), or micellar electrokinetic chromatography [75], particularly where the common carrier is a diphtheria toxoid. Resolution of the conjugate and the carrier can be improved by increasing borate concentration during analysis.

Problems solved by technology

The choice of a common carrier for multivalent vaccines thus increases the carrier suppression risks significantly when compared to the monovalent vaccine or when compared to conjugates that use different carrier proteins.